TumorsAlterInflammation and ImpairDermalWoundHealing in FemaleMice.

Institute for Behavioral Medicine Research, Ohio State University Wexner Medical Center, Columbus, OH, United States of America.

2

Department of Psychiatry and Behavioral Health, Ohio State University, Columbus, OH, United States of America.

3

Department of Neuroscience, Ohio State University, Columbus, OH, United States of America.

4

Center for WoundHealing and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, IL, United States of America.

5

Deparment of Biosciences, College of Dentistry, Ohio State University, Columbus, OH, United States of America.

6

Department of Biobehavioral Health and College of Nursing, Pennsylvania State University, University Park, PA, United States of America.

7

College of Dentistry, Oregon Health and Sciences University, Portland, OR, United States of America.

Abstract

Tissue repair is an integral component of cancer treatment (e.g., due to surgery, chemotherapy, radiation). Previous work has emphasized the immunosuppressive effects of tumors on adaptive immunity and has shown that surgery incites cancer metastases. However, the extent to which and how tumors may alter the clinically-relevant innate immune process of woundhealing remains an untapped potential area of improvement for treatment, quality of life, and ultimately, mortality of cancer patients. In this study, 3.5 mm full-thickness dermal excisional wounds were placed on the dorsum of immunocompetent femalemice with and without non-malignant flank AT-84 murine oral squamous cell carcinomas. Wound closure rate, inflammatory cell number and inflammatory signaling in wounds, and circulating myeloid cell concentrations were compared between tumor-bearing and tumor-free mice. Tumors delayed wound closure, suppressed inflammatory signaling, and altered myeloid cell trafficking in wounds. An in vitro scratch "wounding" assay of adult dermal fibroblasts treated with tumor cell-conditioned media supported the in vivo findings. This study demonstrates that tumors are sufficient to disrupt fundamental and clinically-relevant innate immune functions. The understanding of these underlying mechanisms provides potential for therapeutic interventions capable of improving the treatment of cancer while reducing morbidities and mortality.

Absolute circulating myeloid cell concentrations (CBC) with and without wounding. Average (±SEM) circulating (A) total white blood cells, (B) neutrophils, and (C) monocytes in tumor-bearing and -free mice with and without dermal wounding. n = 8-10/group; *p<0.05 within the same cancer treatment between wounding treatments; #p<0.05 between cancer treatments with same wound treatment; &p<0.05 within the tumor groups between Days 1 & 5.